The mechanism for the profound immunodeficiency in HIV infection remains unclear. Three major observations in HIV disease pathogenesis are 1) there is accelerated spontaneous lymphocyte apoptosis, which involves CD4 and CD8 T cells, 2) there is aberrant cytokine secretion, with discordance in the secretion of the two Th1 type of cytokines, IL-2, which is reduced and IFN-gamma, which is increased and 3) there is persistent virus replication even in the period of clinical latency. Furthermore it has been established in the murine model and in man that CD4 crosslinking (CD4XL) results in activation induced lymphocyte cell death or apoptosis. This proposal aims to test the hypothesis that in HIV infection, aberrant cytokine secretion is a major pathogenic mechanism contributing to immunologic anergy, quantitative loss of lymphocytes by apoptosis and maintenance of viral load. The rationale for this hypothesis is based on the assumption that ligation of CD4 molecules by HIV envelope protein gp 120 occurs in vivo resulting in CD4XL which is facilitated by circulating anti-gp 120 antibodies. Studies in our laboratory have shown that if CD4XL is performed in peripheral blood mononuclear cells of healthy volunteers, induction of apoptosis occurs. Concurrently, there is upregulation of Fas, the apoptosis inducing antigen and of cytokines TNF-alpha and IFN-gamma. TNF-alpha is known to upregulate virus expression in latently infected cells, and synergizes with IFN-gamma in this activity. Thus it is logical to assume that CD4XL can lead not only to apoptosis but also to spread of virus infection by cytokine-mediated activation of latently infected cells. These observations, coupled with our prior findings that HIV- gpl2O/CD4 interaction in T cells leads to inhibition of IL-2 synthesis, indicates that this could be a highly significant mechanism for functional unresponsiveness and lymphocyte depletion in HIV infection. In this continuation application to study HIV-infected children, we will explore the inter-relationship between cytokines, virus load and apoptosis, coupled with phenotypic markers and functional responses in patients' lymphocytes. We will correlate these findings with the patients' disease status using well defined criteria for disease progression. In particular, children classified as slow progressors will be compared with rapid progressors. More importantly we will investigate the effect of various biologicals for their ability to reverse these defects. We believe that elucidation of the pathogenic mechanisms involved in the processes mentioned above should facilitate in the development of rational therapeutic strategies for this disease.